Cancer stem cells (also known as tumor-initiating cells) are implicated in tumor progression, metastasis, and recurrence. Like normal adult stem cells, CSCs are rare, self-renew, and can reconstitute the tissue from which they are derived. And perhaps because they are slow cycling, they are also notoriously resistant to standard therapies.
The Wnt signaling pathway has been implicated in cancer for 30 years, says Sanjeev Satyal, Ph.D., director of cancer biology at OncoMed Pharmaceuticals. The company has identified what it says are perhaps the first therapeutic agents that target that pathway.
According to Dr. Satyal, the Wnt antagonist that OncoMed expects to have in clinical trials next year is fairly unique in that its mechanism of action works by causing differentiation of the cancer stem cells. “A lot of drugs exist out there and they’re just basically sledgehammers that target the bulk of the tumor but do an inefficient job of causing differentiation.”
The question of what exactly is a “cancer stem cell” plagues academic clinicians like Johns Hopkins’ William Matsui, M.D. “Besides tumorogenicity, what other properties might these things have? Are they responsible for metastatic disease? Or progression of cancers? Are they responsible for chemoresistence? Are they derived from normal stem cells? Do mature tumor cells de-differentiate to make these things? Are they mesenchymal in phenotype with an epithelial tumor?
“All those things are questions that have not been adequately addressed. It’s likely that the answers to those questions are probably different for different diseases.” This leads to confusion in the field, and sometimes resistance to the cancer stem cell concept itself.
The problem is especially evident when designing a clinical trial. Unlike going after a target like BRAF or PI3 kinase to eliminate a tumor, it’s “like you’re testing a novel compound within the context of a novel hypothesis—the foundation is unclear,” Dr. Matsui says. “So it becomes even doubly difficult to do these kinds of trials.”
Whether the cells she derives in the lab are true cancer stem cells is a question that doesn’t seem to bother MacroGenics’ senior vp for stem cell research, Jennie Mather, Ph.D., Raven Biotechnologies, which Dr. Mather founded, developed techniques to isolate and expand stem-like cells from various cancers, amassing a portfolio of CSLC lines (along with a host of monoclonal antibodies that target them). When Raven was purchased by MacroGenics in 2008, these formed the basis of the merged company’s cancer stem-like cell platform.
MacroGenics has a strong antibody-engineering program, allowing it to create “dual-specificity antibody-like therapeutic proteins capable of targeting multiple different epitopes with a single recombinant molecule,” according to the company. Several antibody-based drug candidates, discovered and developed using CSLCs, are presently undergoing preclinical evaluation,” notes CEO Scott Koenig, M.D., Ph.D.